Oncotarget

Research Papers:

Combinatorial BTK and MALT1 inhibition augments killing of CD79 mutant diffuse large B cell lymphoma

Daniel Nagel, Miriam Bognar, Andrea C. Eitelhuber, Kerstin Kutzner, Michelle Vincendeau and Daniel Krappmann _

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Oncotarget. 2015; 6:42232-42242. https://doi.org/10.18632/oncotarget.6273

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Abstract

Daniel Nagel1, Miriam Bognar1, Andrea C. Eitelhuber1, Kerstin Kutzner1, Michelle Vincendeau1 and Daniel Krappmann1

1 Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany

Correspondence to:

Daniel Krappmann, email:

Keywords: lymphoma therapy, combination therapy, DLBCL, BTK, MALT1

Received: June 19, 2015 Accepted: September 30, 2015 Published: November 02, 2015

Abstract

Survival of activated B cell-subtype (ABC) of diffuse large B cell lymphoma (DLBCL) is driven by chronic B cell receptor (BCR) signaling that activates the canonical NF-κB pathway. Inhibition of BTK by Ibrutinib has been shown to kill ABC DLBCL cells that carry activating mutations in the BCR adaptor CD79. However, mutations in BTK or in downstream components such as CARMA1/CARD11 can render lymphomas Ibrutinib resistant. Therefore, we assessed here the simultaneous inhibition of BTK and the protease MALT1 that acts downstream of CARMA1 and is essential for ABC DLBCL tumor growth. We show that in CD79 mutant cells BTK is a crucial upstream regulator of MALT1, but dispensable in CARMA1 mutant ABC DLBCL. Combined inhibition of BTK by Ibrutinib and MALT1 by S-Mepazine additively impaired MALT1 cleavage activity and expression of NF-κB pro-survival factors. Thereby, combinatorial Ibrutinib and S-Mepazine treatment enhanced killing of CD79 mutant ABC DLBCL cells. Moreover, while expression of oncogenic CARMA1 in CD79 mutant cells conferred Ibrutinib resistance, double mutant cells were still sensitive to MALT1 inhibition by S-Mepazine. Thus, based on the genetic background combinatorial BTK and MALT1 inhibition may improve effectiveness of therapeutic treatment and reduce the chances for the development of drug resistances.


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